The experiments of this application are designed to elucidate the roles that the TAM receptor tyrosine kinases - Tyro 3, Axl, and Mer - play in the homeostatic regulation of innate immunity. We have discovered that these receptors, together with their agonists Gas 6 and Protein S, are essential intrinsic inhibitors of the inflammatory response to infection. Tyro 3, Axl, and Mer are expressed by macrophages and dendritic cells (DCs). These cells respond to invading bacteria and viruses by producing a panoply of pro-inflammatory and inflammatory cytokines, which, while essential to the defeat of pathogens, are also injurious to normal cells and tissues. If unchecked at the end of the innate immune response, production of cytokines such as TNF-1 leads to chronic inflammatory disease and autoimmunity. The proposed studies exploit a powerful set of genetic reagents - mutant mice that lack the function of each of the receptors and of the activating ligands. As adults, these mice display devastating immune deficits, including lymphoproliferation marked by severe splenomegalogy and lymphadenopathy, systemic hyperactivation of both antigen-presenting cells and of B and T lymphocytes, defects in Natural Killer cell function, and broad-spectrum autoimmune disease. We will investigate the cellular and molecular basis of these phenomena. We will determine the relative contributions of Gas6 and Protein S to TAM receptor activation, and investigate the biochemical mechanisms that underlie suppression of innate immune responses by TAM signaling. We have found that a central mechanism of TAM-mediated suppression involves activation of the transcription factor STAT1 - which is also initially required to activate cytokine production. This sets up a classic negative feedback loop for the regulation of inflammation. We will also elucidate the role that TAM receptors play in triggering the phagocytosis and clearance of apoptotic cells, and dissect the extracellular and intracellular components of the pathway through which the receptors receive and transduce signals required for this process. Together, these studies will provide basic insights into a new signaling system of critical importance to the regulation of immune responses and the development of autoimmunity. Relevance: Autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis exact a major toll on human health. Our studies have revealed that the TAM signaling system is a key regulator of the physiology of the cells that become chronically activated in these diseases, that deficient TAM signaling contributes to the development of autoimmunity, and that hyper-activation of TAM signaling may play a role in sepsis. This receptor system is therefore a novel and attractive target for therapeutic modulation and intervention in disease treatment.